The role of compounds of plant origin in developing new medicinal preparations has evoked unprecedented interest in recent years. It is dealt with in numerous studies that have identified compounds showing a broad spectrum of biological activities, such as flavonoids, flavins, and catechins, among others.
By far the greatest interest has been raised lately by green tea polyphenols, most of them catechins exhibiting a wide spectrum of protective effects. Aqueous extract of green tea contains epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epicatechin (EC).
It is common knowledge that EGCG as an antioxidant is 100 time more effective than vitamin C and 25 as effective as vitamin E (α-tocopherol). The antioxidant qualities of catechins derive from their chemical origin, specifically, a multitude of hydroxyl groups turning these compounds into molecular traps for free radicals that damage the structure of the cell DNA and the cell membranes. In fact, this is the primary quality that drew close attention to EGCG as a biologically active substance. To this day, the capacity of EGCG and other tea catechins to protect healthy cells from oxidative stress is one of the much studied subjects.
Powerful anti-proliferative potential is a further important quality of EGCG targeted at all cells that stimulate expression of signal cascades on which the growth and number of cells of a particular type depends. Modulation of these processes by catechins turns them into powerful anti-inflammatory, anti-proliferative, and anti-angiogenic natural components (Hirofumi Tachibana (2011), “Green Tea Polyphenol Sensing,” Proc. Jpn. Acad., 87, 66-80; Nurulain T. Zaveri (2006), “Green Tea and its Polyphenolic Catechins: Medicinal Uses in Cancer and Noncancer Applications,” Life Sciences, 78, 2073-2080).
Maximum possible tea drinking during the day results in EGCG concentration increasing to 326 ng/ml in human plasma. EGCG semi-ejection time is between 5 and 5.5 hours, much longer than it is for other catechins. Side effects from intake of epigallocatechins begin to show up at very large doses in excess of grams.
Numerous studies are presently carried out to explore the properties and effects of green tea catechins. For example, data were produced a short while ago on the antiviral activity of green tea catechins relative to various viruses. Activity of catechins was studied in respect of herpes simplex viruses, adenoviruses, flu viruses, and human immunodeficiency viruses (Li S., Hattori T., Kodama E. N. (2011), “Epigallocatechin Gallate Inhibits the HIV Reverse Transcription Step,” Antivir. Chem. Chemother., 21(6), 239-243).
It was demonstrated that catechins in in vitro systems suppress significantly the infective activity of the herpes simplex virus, mostly at the stage of virus attachment and penetration into the host cell, and also at later stages of viral infection (Cheng H. Y., Lin C. C., Lin T. C. (2002), “Antiviral Properties of Prodelphinidin B-2 3,-O-Gallate from Green Tea Leaf,” Antivir. Chem. Chemother., 13 (4), 223-229).
In respect of flu infection, Korean researchers published recently their findings on antiviral activity of green tea catechins against the viruses of flu A (H1N1 and H3N2) and flu B. Their studies have shown the hemagglutinin inhibiting activity of some catechins, among which the effect of epigallocatechin was most pronounced. Epigallocatechin altered the physical properties of the viral membrane in MDSC cells, interfering with the life of the virus, suppressing synthesis of the viral RNA, and inhibiting neuraminidase activity. In other words, it actually was active at all stages of infection (Song J. M., Lee K. H., Seong B. L. (2005) “Antiviral Effect of Catechins in Green Tea on Influenza Virus,” Antiviral Res., 68 (2), 66-74). Similar data on antiviral activity of epigallocatechin were obtained at the Influenza Research Institute, Russian Academy of Medical Sciences, in in vitro systems. Work now continues to study the mechanisms of antiviral activity of epigallocatechin and conduct research on animal models.
In addition, data were obtained on antithrombotic activity of catechins. In this respect, epigallocatechin is the most active catechin of all (Kang W. S., Lim I. H., Yuk D. Y., Chung R. Y., Park J. B., Yoo H. S., Yun Y. P. (1999), “Antithrombotic Activities of Green Tea Catechins and Epigallocatechins Gallate,” Thromb. Res., 96 (3), 229-237), a quality that is extremely important for treating flu because the pathogenic mechanisms of flu infection development are known to affect the vascular system and consequent aggregation of thrombocytes that, in turn, causes frequent flu complications such as infarctions and strokes.
It is held to be a proven fact today that the anti-inflammatory activity of EGCG is based on its capacity to block cytokine-dependent pathways of stimulation of pathological cell proliferation.
Mention must also be made of the capacity of EGCG to increase the general immune reactivity of the organism.
Understandably, the general immune status is very important for full-scale anti-inflammatory reaction in any organ or tissue, and disruption of immune response is a key component in the pathogenesis of many hyperplastic and infectious diseases,
The immunomodulating properties of EGCG consist, first, in normalizing the pathological immune response of the organism, in particular, during allergic reactions. Besides, EGCG restores the balance of Th1 and Th2 subtypes of T-helper lymphocytes that have an important part in the immune response (V. I. Kiselev, A. A. Liashenko (2005), “Molecular Mechanisms Regulating Hyperplastic Processes,” Dimitrade Graphic Group Publishers, Moscow).
Anti-inflammatory activity of EGCG is, however, only one of the numerous biological activities of this compound.
Another critical property of EGCG is its capacity, on the one hand, to suppress pathological cell growth caused indirectly by polypeptide growth factors (in particular, epidermal growth factor) and, on the other hand, set off selective apoptosis of cells having an abnormally high proliferative activity. EGCG is, therefore, a powerful blocker of hyperplastic processes in epithelial tissues of different origins (Sah J. F., Balasubramanian S., Eckert R. L., Rorke E. A. (2004), “Epigallocatechin-3-gallate Inhibits Epidermal Growth Factor Receptor Signaling Pathway,” J. Biol. Chem., 279, 12755-12762; Masuda M., Suzuki M., Lim J. T. E., Weinstein I. B. (2003), “Epigallocatechin-3-gallate Inhibits Activation of HER-2/neu and Downstream Signaling Pathways in Human Head and Neck and Breast Carcinoma Cells,” Clin. Cancer Res., 9, 3486-3491).
In addition, EGCG expressly slows down the pathological growth of blood vessels (pathological neoangiogenesis), a process that frequently accompanies hyperplastic processes (Sylvie Lamy, Denis Gingras, Richard Beliveau (2002), “Green Tea Catechins Inhibit Vascular Endothelial Growth Factor Receptor Phosphorylation,” Cancer Res., 62, 381-385).
As the situation is today, the onto-protective properties of EGCG may be considered proven as a fact and well documented in studies. Also established reliably is the capacity of EGCG to block molecular mechanisms causing pathological increase in the number of cells (pathological proliferation), pathological neoangiogenesis (growth of vessels), and rise in invasive activity of transformed cells. By now, a large number of molecular targets inhibited by EGCG and causing indirectly all stages of the pathogenesis of hyperplastic processes and malignant growth have been identified. Biological activity of EGCG and other tea catechins has been shown in experimental, clinical, and large-scale epidemiological studies in respect of a vast number of pre-tumorous and tumorous diseases of the mammary gland, ovaries, cervix of the uterus, endometrium, prostate, skin, gastrointestinal tract (mouth, esophagus, stomach, small and large intestines, liver, and pancreas), and lungs (Yang C. S., Landau J. M., Huang M. T., Newmark H. L. (2001) “Inhibition of Carcinogenesis by Dietary Polyphenolic Compounds,” Annu. Rev. Nutr., 21, 381-406; Fujiki H., Suganuma M., Okabe S., et al. (1996) “Japanese Green Tea as a Cancer Preventive in Humans”).
A majority of observations confirming the wide spectrum of biological properties of epigallocatechins has been made in in vitro experiments. Maximum activity of EGCG in experiments with cell lines was recorded at concentrations of 10 to 50 μm (Naghma Khan, Farrukh Afaq, Mohammad Saleem, Nihal Ahmad, and Hasan Mukhtar (2006), “Targeting Multiple Signaling Pathways by Green Tea Polyphenol Epigallocatechin-3-Gallate,” Cancer Res, 66 (5)).
While the maximum concentration of EGCG in the plasma of patients taking preparations containing green tea catechins did not exceed 1 μm, higher doses caused side effects, without, however, affecting significantly the content of EGCG in blood (H.-H. Sherry Chow, Yan Cai, David S. Alberts, et al. (2001), “Polyphenon E Single-dose Administration of Epigallocatechin Gallate and Phase I Pharmacokinetic Study of Tea Polyphenols Following,” Cancer Epidemiol. Biomarkers Prev., 10, 53-58).
Researchers studying the pharmacokinetics of EGCG reach the conclusion that the above effect is due to the low bioavailability of catechins. According to various sources, bioavailability of catechins is not higher than 1%. Because of this bioavailability, peroral use of catechins cannot assure the desired therapeutic level of catechins in target organs and hence a steady curative effect. For this reasons, many attempts are being made to achieve improvements in the catechin effect by developing various catechin-based formulations (Imtiaz A. Siddiqui, Vaqar M. Adhami, Dhruba J. Bharali, Bilal B. Hafeez, Mohammad Asim, Sabih I. Khwaja, Nihal Ahmad, Huadong Cui, Shaker A. Mousa, and Hasan Mukhtar (2009), “Introducing Nanochemoprevention as a Novel Approach for Cancer Control: Proof of Principle with Green Tea Polyphenol Epigallocatechin-3-Gallate,” Cancer Res., 69(5), 1712-1716; Kristin R. Landis-Piwowar, Congde Huo, Di Chen, Vesna Milacic, Guoqing Shi, Tak Hang Chan and Q. Ping Dou (2007), “A Novel Prodrug of the Green Tea Polyphenol Epigallocatechin-3-Gallate as a Potential Anticancer Agent,” Cancer Res., 67, 4303-4310).
These inventors have demonstrated that EGCG incorporated into nanoparticles on the basis of lactic acid polymers and polyethylene glycol has the same pharmacological activity in doses approximately 10% of the doses of free EGCG and above that of preparations that are not part of formulations. These data were reproduced on cell lines and also on in vivo models when the preparation was administered intraperitoneally. The data obtained give certainty to assumptions that increasing bioavailability causes a significant increase in biological effects. The researchers, though, do not cite any data to show that an increase in the dose of nano-encapsulated EGCG helps make the preparation pharmacologically active in comparison with free EGCG. Furthermore, their invention has a significant deficiency owned up to by the inventors themselves. Actually, the polymers used in their study are very unstable in the acidic medium of the stomach, so much so that they have to be used in injections only. An attempt was made to use a liposome form of EGCG (Jia-You Fang, Woan-Ruoh Lee, Shing-Chuan Shen, Yen-Ling Huang (2006), “Effect of Liposome Encapsulation of Tea Catechins on their Accumulation in Basal Cell Carcinomas,” Journal of Dermatological Science, 42, 101-109). This composition, though, produced a positive effect when used externally and subcutaneously only.
These inventors consider a recent pharmaceutical composition on the basis of lipidic particles that help to almost double the oral bioavailability of EGCG (Adam Smith, Brian Giuntac, Paula C. Bickford, Michael Fountaine, Jun Tana, and R. Douglas Shytle (2010), “Nanolipidic Particles Improve the Bioavailability and α-Secretase Inducing Ability of Epigallocatechin-3-Gallate (EGCG) for the Treatment of Alzheimer's Disease,” International Journal of Pharmaceutics, 389, 207-212) to be the closest related prior art of their invention. Doubling bioavailability, though, is incapable of tapping the pharmaceutical potential of EGCG in full measure. For this reason, it is still a priority to develop EGCG formulations that increase EGCG bioavailability and are suitable for peroral use.